PROJECT SUMMARY Diabetes is a disease that affects millions worldwide, and results from an inability to regulate blood glucose. ?-cells residing in the islets of Langerhans in the pancreas control glucose levels through synthesis and secretion of insulin. However, this ability is lost in diabetes due to dysfunction or loss of ?-cells. Better understanding of the mechanisms that control ?-cell development and function will inform the treatment of diabetes. ?-adrenergic receptors are key mediators of physiological responses to the sympathetic nervous system, and are abundantly expressed in the pancreas throughout life. However, the functions of adrenergic receptors in pancreas development have not been studied. This has significant public health implications as ?- adrenergic receptor antagonists (?-blockers) are used to treat cardiovascular disease and hypertension in pregnant mothers, but the effects on fetal development remain unknown. Additionally, chronic inhibition of ?- adrenoreceptors has adverse side-effects on glucose regulation and is a diabetes risk factor, but the underlying mechanisms have not been identified. Thus, there is a critical need to understand the essential roles of ?-adrenergic receptors in both islet development and glucose homeostasis. Preliminarily, we have identified a tissue-specific role for the ?-2 adrenergic receptor (Adrb2) in the development of the pancreatic islets of Langerhans, potentially by limiting vascular growth. We also find that pancreas-specific deletion of Adrb2 elicits functional defects in glucose tolerance and insulin secretion in mature mice. The overall goal of this proposal is to identify and characterize the mechanisms by which pancreas-specific Adrb2 expression controls islet development and glucose homeostasis. In Aim 1, we will assess the consequences of pancreas-specific Adrb2 deletion on islet morphology and vascularization, and define the signaling mechanisms by which Adrb2 regulates islet development. In Aim 2, we will address the effects of pancreas-specific Adrb2 loss on glucose homeostasis and insulin secretion in mature animals, and we will identify the molecular mechanisms by which Adrb2 signaling in ?-cells influences insulin secretion. This study is the first to address developmental functions of ?-adrenergic receptors in islets, classically studied in adult physiological responses, and to define a pancreas-specific role for ?-adrenergic signaling in glucose homeostasis. Our findings have the potential to establish a new line of research in current translational efforts to treat metabolic disorders.